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US2908694A - 7-substituted thio-4-androstenes - Google Patents

7-substituted thio-4-androstenes Download PDF

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Publication number
US2908694A
US2908694A US804106A US80410659A US2908694A US 2908694 A US2908694 A US 2908694A US 804106 A US804106 A US 804106A US 80410659 A US80410659 A US 80410659A US 2908694 A US2908694 A US 2908694A
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Prior art keywords
methylthiotestosterone
acetoxy
preparation
androstenes
solution
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Expired - Lifetime
Application number
US804106A
Inventor
Robert E Schaub
Martin J Weiss
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Wyeth Holdings LLC
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American Cyanamid Co
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Priority to US804106A priority Critical patent/US2908694A/en
Application granted granted Critical
Publication of US2908694A publication Critical patent/US2908694A/en
Priority to BE589396A priority patent/BE589396A/en
Priority to GB11973/60A priority patent/GB917944A/en
Priority to NL250219A priority patent/NL106961C/xx
Priority to DEA34381A priority patent/DE1128424B/en
Priority to FR837366A priority patent/FR586M/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J31/00Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J75/00Processes for the preparation of steroids in general

Definitions

  • This invention relates to new steroids of the androstene-series. More particularly, it relates to7-alkylthio- 4-androstenes and 7-alkenylthio l-androstenes land methods of preparing .the same.
  • R is a member of the group consisting of hydrogen, lower ,alkanoyl, cycloalkyl lower alkanoyLand aroyl radicals and R is a member of the group consisting of lower alkyl and lower alkenyl radicals.
  • the compoundscf the present invention are crystalline solids having relatively high melting points. They are relatively insolublein water and somewhat soluble in the usual organic solvents. They are crystallizable from mixtures of ketones and hydrocarbon solvents.
  • the present compounds are prepared by reacting a 17fl-lower alkanoyl-4,6-androstadiene-3-one with a lower alkyl or lower al-kenyl mercaptan.
  • the reaction is preferably carried out in a solvent such as glacial acetic acid in the presence of a mineral acid catalyst.
  • the reaction takesplace at a-tempenaturebetweenO and 50 C. and is usually complete in a matter of 2 or 3 hours to several days.
  • the product is recovered by evaporation of the solvent used in. the reaction followed by taking up the residue in a further organicsolvent. Following removal of the latter solvent, the desired product is further purified by crystallization.
  • the process of this invention proceeds under steric influences and stereoisomers are formed, howev er, one is obtained inpredominate amount.
  • the isomer obtained in predominant amount has in each case been characterized herein as possessing the alpha configuration of the 7 lower la-lkylthio or lower alkenylthio group.
  • This configuration has been designated in order to provide a more complete exposition of the present invention, and in order that the specification shall constitute a more useful contribution to the art.
  • the designated configuration ofthe 7'-lower alkylthio or lower alkenylthio group is based uponsan analysis of molecular rotation data presently appearing in the chemical literature, and is therefore not to be interpreted except in relation to the-state of the, artpresently known to organic chemists. It will be apparent that no part of the specification will be materially defective if it should later 'be in the field.
  • the compounds of the present invention can be used in'the form of tablets, fills, powders, and so forth, which .mayhlso contain starch, excipients, and other ingredients necessary in the compounding of such dosage forms. .They may 'be used singly or in combination with other steroids.
  • lower alkyl radical is intended to cover saturated hydrocarbon radicals having 1 to 6 carbon atoms.
  • lower a-lkanoyl radical is intended to cover the acyl radicals obtained from alkanoic acids. having 1 to 14 carbon atoms and the term cycloalkyl lower alkanoyl radical is intended to cover acyl radicals obtained from cycloalkyl substituted alkanoic acids having 7 to 11 carbon atoms with .5 101'. 6 carbon atoms in the cycloalkyl group.
  • EXAMPLE 5 Preparation of 17p-acetogcy-7a-n-propylthi0-4-androsten- -one A solution of 0.6 g. of 17/3-acetoxy-4,6-androstadien-3- one, 1 ml. of concentrated hydrochloric acid and 5 ml. of isopropylmercaptan in 25 ml. of glacial acetic acid is treated according to the procedure described in Example 1 to give 17 3-acetoxy-7u-isopropylthio-4-androsten-3-one.
  • EXAMPLE 7 Preparation of 7a-methylthiotestosterone propionate A solution of 1.0 g. of 7a-methylthiotestosterone in ml. of reagent pyridine is treated with 5 ml. of propionic anhydride and allowed to stand overnight at room temperature. The mixture is poured into water, extracted with methylene chloride, the methylene chloride extract washed successively with saturated sodium bicarbonate solution and water, and finally evaporated to dryness under reduced pressure to furnish 7a-methylthiotestosterone propionate as white crystals;
  • EXAMPLE 8 Preparation of 7a-methylthiotestosterone isobutyrate A solution of 0.5 g. of 7a-methylthio-testosterone in 5 ml. of reagent pyridine is treated with 3 g. of isobutyric anhydride according to the procedure described in Example 7 to give 7a-methylthiotestosterone isobutyrate;
  • a 239 mp max (e14,800); 1 1730, 1670, 1625, 1195 cm.-
  • EXAMPLE 11 Preparation of 7a-methylthiotestosterone decanoate A solution containing 1 g. of 7u-methylthiotestosterone in 25 ml. of dry benzene is treated with 3 ml. of dry pyridine and 4 g. of decanoyl chloride according to the procedure described in Example 10 to give 7oc-methylthiotestosterone decanoate;
  • R is a member of the group consisting of hydrogen, lower alkanoyl, cycloalkyl lower alkanoyl and aroyl radicals and R is a member of the group consisting of lower alkyl and lower alkenyl radicals.
  • R is a lower alkanoyl radical and R is a lower alkyl radical.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

L difi i Patented Oct. 13, 1959 United states Patent Ofice r 7-sIJBs'rITUr D THI'G-d-ANDROSTENES Robert Sc'ha u'b, Parainus, and Martin J. Weiss, Oradell, N.J., assignors to American Cyanamid Company, New York, N.Y., acorporation of Maine No' Drawing. Application April 6, 1959 Serial No. 804,106
"6 Claims.' (Cl. 260-'397.4)
This invention relates to new steroids of the androstene-series. More particularly, it relates to7-alkylthio- 4-androstenes and 7-alkenylthio l-androstenes land methods of preparing .the same.
The .use of steroids for their glucocorticoid activity in the treatment of collagen diseases is well :known. Their use, however, as .nonor low-virilizing anabolic agents is less well known. Wehave now found t-hatthe steroids described hereinafter possess these properties and are therefore useful as anabolic agents.
The compoundsof the present invention may be illustrated by the general formula:
in which R is a member of the group consisting of hydrogen, lower ,alkanoyl, cycloalkyl lower alkanoyLand aroyl radicals and R is a member of the group consisting of lower alkyl and lower alkenyl radicals.
The compoundscf the present invention are crystalline solids having relatively high melting points. They are relatively insolublein water and somewhat soluble in the usual organic solvents. They are crystallizable from mixtures of ketones and hydrocarbon solvents.
The present compounds are prepared by reacting a 17fl-lower alkanoyl-4,6-androstadiene-3-one with a lower alkyl or lower al-kenyl mercaptan. The reaction is preferably carried out in a solvent such as glacial acetic acid in the presence of a mineral acid catalyst. The reaction takesplace at a-tempenaturebetweenO and 50 C. and is usually complete in a matter of 2 or 3 hours to several days. The product is recovered by evaporation of the solvent used in. the reaction followed by taking up the residue in a further organicsolvent. Following removal of the latter solvent, the desired product is further purified by crystallization.
The process of this invention proceeds under steric influences and stereoisomers are formed, howev er, one is obtained inpredominate amount. The isomer obtained in predominant amount has in each case been characterized herein as possessing the alpha configuration of the 7 lower la-lkylthio or lower alkenylthio group. This configuration has been designated in order to provide a more complete exposition of the present invention, and in order that the specification shall constitute a more useful contribution to the art. However, the designated configuration ofthe 7'-lower alkylthio or lower alkenylthio group is based uponsan analysis of molecular rotation data presently appearing in the chemical literature, and is therefore not to be interpreted except in relation to the-state of the, artpresently known to organic chemists. It will be apparent that no part of the specification will be materially defective if it should later 'be in the field.
The compounds of the present invention can be used in'the form of tablets, fills, powders, and so forth, which .mayhlso contain starch, excipients, and other ingredients necessary in the compounding of such dosage forms. .They may 'be used singly or in combination with other steroids.
In the present application the term lower alkyl radical is intended to cover saturated hydrocarbon radicals having 1 to 6 carbon atoms. The term lower a-lkanoyl radical is intended to cover the acyl radicals obtained from alkanoic acids. having 1 to 14 carbon atoms and the term cycloalkyl lower alkanoyl radical is intended to cover acyl radicals obtained from cycloalkyl substituted alkanoic acids having 7 to 11 carbon atoms with .5 101'. 6 carbon atoms in the cycloalkyl group.
' The following examples illustrate in detail the prepara- ,tion.of the 7-allcylthioand 7-alkenylthioandrostenes of ,the. present invention.
EXAMPLE 1 Preparation of 17,8-acet0xy-7a-methylthio-4-androsten-3- one A solution of 0.6 g. of 17/3-acetoxy-4,6-androstadien- 3-one [C. Djerassi et -al., J. Am. Chem. Soc., 72, 4538 (l-950)], 1 ml. of concentrated hydrochloric acid and 5 ml. of methylmercaptan in 25 m1. of glacial acetic acid is allowed to stand at 58 C. for 48 hours. The reaction miXture is evaporated to dryness under reduced pressure and the-concentrate is diluted with methylene chloride and washed with excess. saturated sodium bicarbonate solution, and then with water. The organic phase is dried with anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a glass. Crystallization from acetone-petroleum ether gives 17fl-acetoxy 7oz methylthio-4- androsten-3-one. Recrystallization from acetone-petroleum ether afiords white crystals XE SQ 240 inn (e=1 5,500); 1/ 1730, 1675, 1620, 1240 (cm- EXAMPLE 2 Preparation of .7 7 B-acetoxy 7a ethylzhi0-4-andr0sten-3- one A solution of 0.865 g. of 17pacetoxy-4,6-androstien- 3-one, '2 ml. of concentrated hydrochloric acid and 10 ml. ,OfethyImerCaptan in 75 ml. of glacial acetic acid is allowed to stand at 58 C. for 72 hours. The reaction mixtureis evaporated to dryness under reduced pressure and the concentrateis diluted with methylene chloride and washed with excess. saturated sodium bicarbonate solution, and then with Water. The organic phase is dried with anhydrous magnesium sulfate and evaporated rto (dryness under reduced pressure to give a glass. Crystallization from acetone-petroleum ether gives 17,8- acetoxy 7a ethylthio-4-androsten-3 -one. Recrystallization from acetone-petroleum ether gives white crystals;
A E Q4O m 15,800); 11 1730, 1675; 1620, '1240 Cm.
EXAMPLE 3 Preparation of 17B-ocet0xy-7a-mpr0pylthi0-4-androsten- I 3-0ne A solution of 1.3 g. of 17fl-acetoxy-4,6-androstadien-3- one, 2 ml. of concentrated hydrochloric acid and 10 ml.
of n-propylmercaptan in ml. of glacial acetic acid is treated according to the procedure described for the preparation or" 17/3-acetoxy-7a-methylthio-4-androsten-3-one 3 (Example 1) to give 17 3-acetoxy-7a-n-propylthio-4-androsten-3-one as white crystals;
AMeOH y (615,100); 111730, 1675, 1622, 1240 cmr' EXAMPLE 4 Preparation of 17p-acetoxy-7a-allylthio-4-andr0sten-3-one A solution of 1 g. of 17/8-acetoxy-4,6-androstadien-3- one, 2 ml. of concentrated hydrochloric acid and 10 ml. of allylmercaptan in 75 ml. of glacial acetic acid is treated according to the procedure described in Example 1 to give 1718-acetoXy-7oiallylthio-4-a.ndrosten-3-one;
rage 241 111; (615,500); 111730, 1675, 1619, 1241 cm.
EXAMPLE 5 Preparation of 17p-acetogcy-7a-n-propylthi0-4-androsten- -one A solution of 0.6 g. of 17/3-acetoxy-4,6-androstadien-3- one, 1 ml. of concentrated hydrochloric acid and 5 ml. of isopropylmercaptan in 25 ml. of glacial acetic acid is treated according to the procedure described in Example 1 to give 17 3-acetoxy-7u-isopropylthio-4-androsten-3-one.
EXAMPLE 6 Preparation of 7a-methylthiotestosterone A solution containing 0.585 g. of 17p-hydroxy-4,6- androstadien-3-one, 1 ml. of concentrated hydrochloric acid and 5 ml. of methylmercaptan in 25 ml. of dioxane is treated according to the procedure described in Example 1, to give 7a-methylthiotestosterone;
max
(e=15,200); 113450, 1670, 1620 cm.-
EXAMPLE 7 Preparation of 7a-methylthiotestosterone propionate A solution of 1.0 g. of 7a-methylthiotestosterone in ml. of reagent pyridine is treated with 5 ml. of propionic anhydride and allowed to stand overnight at room temperature. The mixture is poured into water, extracted with methylene chloride, the methylene chloride extract washed successively with saturated sodium bicarbonate solution and water, and finally evaporated to dryness under reduced pressure to furnish 7a-methylthiotestosterone propionate as white crystals;
max
EXAMPLE 8 Preparation of 7a-methylthiotestosterone isobutyrate A solution of 0.5 g. of 7a-methylthio-testosterone in 5 ml. of reagent pyridine is treated with 3 g. of isobutyric anhydride according to the procedure described in Example 7 to give 7a-methylthiotestosterone isobutyrate;
A 239 mp max (e14,800); 1 1730, 1670, 1625, 1195 cm.-
4 EXAMPLE 9 Preparation of 7a-methy lthiotestosterone benzoate A solution of 0.6 g. of 7a-methylthiotestosterone in 15 m1. of dry benzene is treated with 2 ml. of dry pyridine and 2 g. of benzoyl chlorideand allowed to stand overnight at room temperature. The mixtureis poured into water, extracted with methylene chloride, the methylene chloride extracts washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, and finally evaporated to dryness under reduced pressure to give 7a-methylthiotestosterone benzoate;
A 228 mp max 1100 cmr EXAMPLE 10 Preparation of 7u-methylthiotestosterone fl-cyclopentylpropionate A solution of 1 g. of 7u-methylthiotestosterone in 25 ml. of dry benzene is treated with 3 ml. of dry pyridine and 3 g. of fl-cyclopentylpropionyl chloride according to the procedure described in Example 9, to give 7a-methylthiotestosterone p-cyclopentylpropionate;
max
(e15,100); 1 1735, 1668, 1620, 1190 cm.-
EXAMPLE 11 Preparation of 7a-methylthiotestosterone decanoate A solution containing 1 g. of 7u-methylthiotestosterone in 25 ml. of dry benzene is treated with 3 ml. of dry pyridine and 4 g. of decanoyl chloride according to the procedure described in Example 10 to give 7oc-methylthiotestosterone decanoate;
by}? 241 my.
We claim: 1. Compounds having the general formula:
O-R CH in which R is a member of the group consisting of hydrogen, lower alkanoyl, cycloalkyl lower alkanoyl and aroyl radicals and R is a member of the group consisting of lower alkyl and lower alkenyl radicals.
2. The compound 175 -acetoxy-7a-methylthio-4androstene-3-one.
3. The compound l7 3-acetoxy 7a allylthio-4-androstene-3-one.
4. The compound 17,8-hydroxy-7a-methylthio-4-androstene-B-one.
5. Compounds having the general formula:
' in which R is a lower alkanoyl radical and R is a lower alkyl radical.
5 6 6. Compounds having the general formula References Cited in the file of this patent OH, UNITED STATES PATENTS OH 011 2,837,543 Dodson et a1. June 3, 1958 5 2,859,222 Dodson et a1. Nov. 4, 1958 0= -S-RI 10 in which R is a lower alkyl radical.
UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,908,694 October 13, 1959 Robert E. Schaub et a1.
It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected belm Column 3, line 19, Example 5, for the heading Preparation of JVB-aceZOwy-7apropyZt/Lz'o-4-androsten-3-one read -Preparatz'0n of J7,8-acezfoz'y-7a-is0pr0pyZt/Li0-4- androsten-3one-.
Signed and sealed this 29th day of March 1960.
[sEALJ Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Oficer. Commissioner of Patents.

Claims (1)

1. COMPOUNDS HAVING THE GENERAL FORMULA:
US804106A 1959-04-06 1959-04-06 7-substituted thio-4-androstenes Expired - Lifetime US2908694A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US804106A US2908694A (en) 1959-04-06 1959-04-06 7-substituted thio-4-androstenes
BE589396A BE589396A (en) 1959-04-06 1960-04-05 New steroids of the androstene series and their preparation
GB11973/60A GB917944A (en) 1959-04-06 1960-04-05 í~-androstenes and method of preparing the same
NL250219A NL106961C (en) 1959-04-06 1960-04-06
DEA34381A DE1128424B (en) 1959-04-06 1960-04-06 Process for the preparation of 7-alkylthio- and 7-alkenylthio-4-androsten-3-ones
FR837366A FR586M (en) 1959-04-06 1960-08-31

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BE (1) BE589396A (en)
DE (1) DE1128424B (en)
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NL (1) NL106961C (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3022323A (en) * 1962-02-20 Y-substituted thio steroids of the
US3074932A (en) * 1960-08-15 1963-01-22 American Cyanamid Co 7-substituted thio steroids
US3098084A (en) * 1961-02-02 1963-07-16 Merck Ag E Anabolic alkylthio-steroids
DE1225638B (en) * 1961-02-02 1966-09-29 Merck Ag E Process for the preparation of 7alpha-alkylthio-17alpha-methyl-testosterones

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2837543A (en) * 1956-10-22 1958-06-03 Searle & Co Pregnene-1-thiol esters and preparation thereof
US2859222A (en) * 1957-12-31 1958-11-04 Searle & Co 7alpha-acylthio substitution products of 4-androsten-3-ones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2837543A (en) * 1956-10-22 1958-06-03 Searle & Co Pregnene-1-thiol esters and preparation thereof
US2859222A (en) * 1957-12-31 1958-11-04 Searle & Co 7alpha-acylthio substitution products of 4-androsten-3-ones

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3022323A (en) * 1962-02-20 Y-substituted thio steroids of the
US3074932A (en) * 1960-08-15 1963-01-22 American Cyanamid Co 7-substituted thio steroids
US3098084A (en) * 1961-02-02 1963-07-16 Merck Ag E Anabolic alkylthio-steroids
DE1225638B (en) * 1961-02-02 1966-09-29 Merck Ag E Process for the preparation of 7alpha-alkylthio-17alpha-methyl-testosterones

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FR586M (en) 1961-06-12
GB917944A (en) 1963-02-13
NL106961C (en) 1963-11-16
BE589396A (en) 1960-10-05
DE1128424B (en) 1962-04-26

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